title: Rotenone induces reductive stress and triacylglycerol deposition in C2C12 cells.
abstract: Environmental rotenone is associated with Parkinson's disease due to its inhibitory property to the complex I of mitochondrial respiration chain. Although environmental pollution has been postulated as a causal factor for the increasing prevalence of obesity, the role of rotenone in the pathogenesis of obesity has not been studied. We employed muscle-derived cell C2C12 as a model and shotgun lipidomics as a tool for lipid analysis and found that treatment with rotenone led to the profound deposition of intracellular triacylglycerol (TAG) in a time- and dose-dependent fashion. The TAG deposition resulted from complex I inhibition. Further studies revealed that rotenone induced mitochondrial stress as shown by decreased mitochondrial oxygen consumption rate, increased NADH/NAD+ ratio (i.e., reductive stress) and mitochondrial metabolites. We demonstrated that rotenone activated fatty acid de novo synthesis and TAG synthesis and ultimately resulted in intracellular TAG deposition. These studies suggested that increased mitochondrial stresses might be an underlying mechanism responsible for TAG accumulation manifest in obesity.
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: He
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.forename: Christopher
authors.initials: C
authors.lastname: Petucci
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gardell
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
mesh_terms: D041721:3T3-L1 Cells; D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D042967:Electron Transport Complex I / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D032342:Muscle Cells / Q000187:drug effects* / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D012402:Rotenone / Q000494:pharmacology*; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D014280:Triglycerides; D012402:Rotenone; D001275:ATP Citrate (pro-S)-Lyase; D042967:Electron Transport Complex I
keywords: ACL; ATP citrate lyase; ETC; FA; GPAT; Mitochondrial complex I; OCR; Obesity; PD; Parkinson's disease; Shotgun lipidomics; T2DM; TAG; TCA; Triacylglycerol; electron transport chain; fatty acid; glycerol-3-phosphate acyltransferase; oxygen consumption rate; triacylglycerol; tricarboxylic acid; type II diabetes mellitus